An interesting relationship between drug absorption and melting point

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Physical Chemistry of Drugs

Background:

• Predicting passive intestinal drug absorption is crucial for drug development.
• Existing models use solubility, partition coefficient, and pK(a).
• Poorly soluble drugs (BCS Class II and IV) present absorption challenges.

Purpose of the Study:

• To investigate the relationship between melting point and passive intestinal drug transport.
• To evaluate melting point as a predictor for drug absorption.
• To introduce a novel melting point-based absorption potential (MPbAP) parameter.

Main Methods:

• Utilized the General Solubility Equation (GSE) to relate melting point to solubility and partition coefficient.
• Analyzed the correlation between melting point, dose, and fraction absorbed (FA).
• Developed and validated the MPbAP parameter using a dataset of 91 drugs.

Main Results:

• Melting point is a reliable physical property for predicting absorption of poorly soluble drugs.
• The MPbAP parameter successfully distinguished well-absorbed (FA>0.5) from poorly absorbed drugs in 90% of cases.
• Lower melting point compounds generally exhibit better absorption than higher melting point compounds.

Conclusions:

• Melting point serves as an advantageous early indicator in drug discovery for absorption potential.
• The MPbAP parameter offers a practical approach to assess drug absorption based on a readily measured property.
• Drug absorption for high-melting-point compounds is more dose-limited than for low-melting-point compounds.